First-line biologic therapy with tumor necrosis factor inhibitors for psoriatic arthritis: a prospective observational study

ABSTRACT BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease that affects multiple joints. It is associated with psoriasis and treated with synthetic and biologic drugs. OBJECTIVE: The objective of this study was to assess the outcomes of patients who received biologic therapy with tumor necrosis factor (TNF) inhibitors in terms of effectiveness, safety, functionality, and quality of life. DESIGN AND SETTING: A prospective observational study was performed at a single center in Belo Horizonte, Brazil. METHODS: Patients with PsA who received their first TNF inhibitor treatment were followed up for 12 months. Disease activity was measured using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Clinical Disease Activity Index (CDAI). Functionality was measured using the Health Questionnaire Assessment (HAQ), and quality of life was evaluated using the European Quality of Life Five Dimensions (EQ-5D). Multiple linear regression was used to identify predictors of the clinical response at 12 months. RESULTS: A total of 143 patients treated with adalimumab or etanercept were evaluated. Most of the clinical measures were significantly improved at 12 months. However, 31%–51% of the patients did not achieve good clinical control. No differences were observed between adalimumab and etanercept, except for poor functionality at 12 months among patients treated with etanercept. The main predictors of a worse clinical response were female sex, etanercept use, poor functionality, or lower quality of life at baseline. The main adverse reactions were alopecia, headache, injection site reaction, sinusitis, flu, dyslipidemia, and infections. CONCLUSION: TNF inhibitor therapy was effective and safe. However, despite improvements in clinical measures, most patients did not achieve satisfactory control of the disease.


INTRODUCTION
Psoriatic arthritis (PsA) is a chronic inflammatory disease that is usually seronegative for rheumatoid factor and has diverse clinical manifestations. 1 The different clinical features are challenging for physicians in terms of diagnosis and treatment. 1,2 Delayed diagnosis of PsA is associated with irreversible damage, and streamlined early treatment with disease-modifying antirheumatic drugs (DMARDs) can slow disease progression and improve physical function and quality of life. 1,3 In Brazil, the treatment of PsA is covered by the Unified Health System (Sistema Único de Saúde, SUS), a national public health system subsidized by taxes, which provides primary, outpatient, and hospital care in addition to drugs and other health technologies for comprehensive treatment. 4,5 Around 210 million people are covered, of which 75% are exclusively assisted by the SUS. PsA patients are attended to by doctors from the public and private sectors (SUS and non-SUS). Their medication is covered by the SUS, health plans, or out-of-pocket expenses.
However, the supply of biologic DMARDs (bDMARDs) is almost entirely realized by SUS pharmacies because of the high cost of these drugs to PsA patients. 4,5 The drugs available through the SUS include nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and conventional synthetic, biologic, and target-specific synthetic DMARDs. 6 NSAIDs and glucocorticoids are usually used to control disease symptoms, such as pain and swelling. DMARDs are immunosuppressive and immunomodulatory agents that can modify the natural course of the disease, including delays in clinical or radiographic progression. bDMARDs, including tumor necrosis factor-alpha inhibitors (adalimumab, etanercept, infliximab, golimumab, and certolizumab) and interleukin-17 inhibitors (secukinumab), are usually prescribed after the failure of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). 6 The advent of tumor necrosis factor inhibitors (TNFis) has resulted in a substantial improvement in the treatment of PsA refractory to csDMARDs, and the efficacy of these agents has been demonstrated in randomized controlled trials. 7 However, limited head-to-head studies have compared the clinical efficacy of these drugs. 8 Despite the benefits observed with biologic TNFis in the last few years, approximately 40% of patients discontinued treatment in the 12 months of follow-up. In addition, the substantial economic impact of TNFi therapy on health systems was observed, accounting for 90% of the PsA treatment cost. 4 Therefore, a realworld evaluation is warranted.
Observational studies are instrumental in complementing the scientific evidence of efficacy and safety provided by randomized controlled trials. 9 Furthermore, in the absence of head-to-head randomized controlled trials comparing two or more bDMARDs, observational studies with a common drug comparator can be used to evaluate and compare these drugs in clinical practice. 10

OBJECTIVE
The objective of this study was to evaluate the outcomes of patients diagnosed with PsA in Brazil who received TNFi therapy in terms of effectiveness, functionality, quality of life, and safety.

Statistical analysis
The sample size was estimated considering the MCID for the HAQ and EQ-5D outcomes for paired samples (baseline and end Descriptive analysis was performed using the frequency distribution, mean, and standard deviation. An independent t-test for two independent groups and a paired t-test for two paired groups were used for continuous variables. Pearson's chi-squared test was used for categorical variables. Multiple imputations addressed missing data. A predictive mean matching method was adopted considering the monotonic pattern observed in the missing data; missing data at 6 months were also missing at 12 months. 18  and diabetes mellitus (n = 22; 15.4%). Other reported comorbidities were gastritis (n = 11; 7.7%), hypothyroidism (n = 10; 7.0%), anxiety (n = 9; 6.3%), and fibromyalgia (n = 6; 4.2%).

Effectiveness, functionality, and quality of life
All clinical measures of disease activity, functionality, and quality of life were significantly improved at 6 and 12 months compared with the baseline among patients treated with adalimumab (P < 0.001). Most clinical measures also showed a statistically significant reduction at 6 and 12 months compared with the baseline among patients treated with etanercept, except for a borderline value in the HAQ at 12 months ( Table 2 and Figure 1). TNFi are presented in Table 4.
According to the BASDAI, patients with herniated disc, depression, gastritis, fibromyalgia, obesity, and hypothyroidism had higher disease activity at baseline. Of these patients, those with depression, gastritis, and obesity had a significantly lower clinical response (GCR) at 12 months (P < 0.05) ( Table 5).
Furthermore, patients with arthrosis, depression, fibromyalgia, gastritis, and herniated disc had poor functionality and lower quality of life at baseline.

Predictors of clinical response
Predictors of a worse CDAI response were female sex, comorbidities, etanercept use, and poor functionality. Predictors of a to the EQ-5D ( Table 6).

Safety
The main adverse reactions reported by the patients were alopecia, headache, injection site reaction, sinusitis, flu, dyslipidemia, and infections. No cases of tuberculosis and herpes zoster were reported ( Table 7).

DISCUSSION
This comparative study was conducted to evaluate the outcomes of PsA patients treated with adalimumab or etanercept in a real-world setting in Brazil. Loss to follow-up was 14.7% at 6 months and 35.7% at 12 months of follow-up, similar to the rates of medication non-persistence in Brazil. 21 Lack of effectiveness and adverse reactions were the main causes of the loss to followup, as described in other studies. [22][23][24] Although adverse reactions contributed to discontinued follow-up, the use of TNFis can be considered safe with manageable adverse reactions. 25 Most clinical measures of disease activity, functionality, and quality of life were significantly improved at 6 and 12 months. A recent network meta-analysis reported the efficacy and acceptable safety profile of bDMARDs for PsA. 26  Several comparative observational studies have been conducted for PsA and reported no differences in the effectiveness of adalimumab and etanercept, except for some outcomes such as lower medication persistence with etanercept. 4,21,24,25,29 In our study, patients treated with adalimumab showed a greater improvement in functionality at 12 months. In addition, despite no significant differences in other outcomes, better results were obtained for disease activity and quality of life when adalimumab was administered.
In Brazil, etanercept was considered a cost-effective option in comparison to adalimumab in the past owing to its lower cost and effectiveness. 30 However, currently, adalimumab is more cost-effective than etanercept and continues to offer some benefits, making it a cost-effective drug. 4,31 Comorbidities, functional disability, and quality of life at baseline have been reported as predictive factors of the EQ-5D response at 12 months of follow-up. 28 In this study, poor functionality at baseline was predictive of worse CDAI response.
Studies have reported that better functionality is associated with a lower level of pain and structural damage and better work productivity, contributing to a good clinical response according to the CDAI. 32      adequate home storage conditions for biopharmaceuticals.
The intrinsic factors of household refrigerators have been suggested to play a role in temperature deviations. 42 The difficulty in the application of biopharmaceuticals by patients should be further investigated.
An important challenge faced by rheumatologists in Brazil is patient access and follow-up, which may be associated with compromised care. 43 Furthermore, the median time to medication access through the SUS for PsA treatment following a medical prescription has been reported to be longer than 2 months. 5 Therefore, additional strategies that can help achieve good disease control should be considered, which may include: This study has some limitations. Skin involvement was not evaluated because the Brazilian clinical guidelines for PsA started to consider this manifestation only after the update in 2018. 6 The BASDAI and CDAI are not specific indices for PsA. However, the BASDAI was used by the Brazilian clinical guidelines for PsA until 2018, and the CDAI has a strong correlation with a specific feature of PsA. 6,14 In addition, laboratory and radiological test results were not obtained as they are not required for drug treatment through the SUS. Finally, the method used to select patients was also a limitation as only individuals who visited the health center were eligible to participate in the study. Therefore, more severe cases of PsA may not have been included, and the results should be interpreted and generalized with caution.

CONCLUSION
The study found that TNFi therapy was effective and safe.
However, despite improvements in clinical measures, most patients did not achieve adequate control of the disease, mainly those with poor functionality and lower quality of life at baseline and comorbidities, such as depression and fibromyalgia.